P49 A REAL-WORLD RETROSPECTIVE-PROSPECTIVE ANALYSIS OF EFFICACY AND SAFETY OF COMBINED IXAZOMIB, LENALIDOMIDE AND DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE NORTHERN ITALY EXPERIENCE
Authors: A. Furlan, M. Cea, R. Zambello, L. Pavan, M Galli, C. Clissa, S. Mangiacavalli, A. Cafro, S. Girlanda, F. Patriarca, C. Minotto, G. Bertoldero, G. Barilà, A. Pascarella, A. Lico, R. Paolini, N. Rabassi, N. Pescosta, M. Porrazzo, G. De Sabbata, A. Pompa, G. Bega, S. Cavallin, F. Guidotti, G. Semenzato, C. Zaina, F. Gherlinzoni
Journal: HemaSphere (2023)

Ixazomib-lenalidomide and dexamethasone (IRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the pivotal Tourmaline MM-1 trial. We conducted an observational analysis of 81 RRMM patients (pts) treated with IRd between January 2017 and May 2021 in 18 Northern Italy centers, with the aim to evaluate efficacy and safety of IRd in real-life. The study comprises a retrospective phase (chart review of the period from ixazomib initiation to enrolment) followed by a 18-month prospective follow-up period. At IRd initiation, 32% of pts were aged ≥75 (median age 72), 30% had an ECOG performance status ≥2, 54% of evaluable (64/81) pts carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)] and/or 1q gain/amp], median number of prior lines of therapy was 2 (1-6) with 57% receiving ≥2 prior lines, 71% were exposed to lenalidomide, 24% were lenalidomide-refractory. Median time from diagnosis was 60 months. At the median of 31 months, 81% of the pts had discontinued treatment, mainly (62%) for progression. Main grade 3-4 adverse events (AEs) were neutropenia (11%) and thrombocytopenia (11%). Non-hematological grade 3-4 AEs were infections, venous thromboembolism, gastrointestinal toxicity, reported in 2 (2.5%), 3 (3.7%) and 4 (5%) pts respectively. Overall, the response rate was 53% (≥VGPR 32%). With a median follow up of 31 months, median PFS (mPFS) was 12 months, ranging from 21 months in pts receiving 1 prior line and 7.4 months in pts receiving >3 prior lines respectively. 1-year OS rate was 53%. By subgroup analysis, extended PFS was observed for pts aged ≥75 (mPFS 26.2 months), with 1 prior line of therapy (21 months), achieving at least a VGPR (21 months), prolonged time (>5 years) from diagnosis to IRd (20 months), without HRCA (18.6 months). An inferior PFS was seen in lenalidomide-refractory pts (4.8 months). At multivariate analysis using Cox’s regression, the only independent prognostic factors for PFS were age ≥75 (HR 0.35, 95% CI: 0.15-0.82, p=0.016), prolonged time (>5 years) from diagnosis (HR 0.29, 95% CI: 0.13-0.65, p=0.03) and refractoriness to a previous lenalidomide-based treatment (HR 2.23, 95% CI: 1.06-4.70, p=0.035). With regards to survival, lenalidomide-refractory pts had a 2-fold increase in the risk of death (HR 2.1, 95% CI: 0.91-4.8, p=0.08). PFS appears to be superior in the older population possibly related to IRd treatment in earlier lines of therapy (52% of pts aged ≥75 had received IRd after 1 prior line and only 24% after >3 lines); notably, 70% of pts aged ≥75 had HRCA. In conclusion, in a real-life population with adverse prognostic characteristics in terms of older age, performance status, cytogenetic risk, exposure and refractoriness to lenalidomide, IRd demonstrated inferior OR rates, rates of ≥VGPR and PFS as compared to the pivotal trial, with a good tolerability profile and no new safety concerns. Favorable PFS outcomes, however, emerged for pts achieving at least a VGPR, with 1 prior line of therapy, prolonged time from diagnosis to IRd, and aged ≥75. Moreover, as emerged from the analysis of the elderly population, treatment with IRd in earlier lines of therapy might overcome the adverse impact of high risk cytogenetics. IRd might, therefore, represent an effective and safe combination in selected RRMM pts with an indolent disease course in early lines of treatment, independent of age.